Whole brain irradiation (WBI) is a common treatment for both primary brain tumors and prevention of metastases. Unfortunately, approximately 50% of the 200,000 cancer patients who receive WBI each year develop progressive cognitive deficits > 6 months after treatment, due to normal tissue damage. The cellular and molecular mechanisms underlying WBI-induced brain injury remain unknown. There are currently no successful treatments or preventative measures against late delayed effects. Blockade of the renin-angiotensin system (RAS) is an attractive therapeutic target, since RAS blockers are well-established in the clinic and were shown previously to ameliorate radiation-induced lung and kidney injury. This proposal will test the efficacy of the angiotensin II type 1 receptor (AT1R) blocker L-158,809 against WBI-induced brain injury. It will determine the effects of AT1R blockade on: i) the WBI-induced inflammatory response, as measured by the expression of pro-inflammatory cytokines, via ELISAs, and indices of microglial proliferation and activation, via IHC, and ii) radiation-induced changes in neurogenesis and the association of precursor cells and the microvasculature in the dentate gyrus, via IHC & stereology. The hypothesis is that WBI-induced inflammatory response is mediated by the brain RAS and, therefore, that RAS blockade will reduce radiation-induced inflammation and injury. The above aims will test the effects of a widely prescribed and well-tolerated drug class, successful results in this animal model can be readily translated to clinical trials that could improve significantly the quality of life for long-term cancer survivors treated with WBI. [unreadable] [unreadable] [unreadable] [unreadable]